GABAergic inhibitory interneurons comprise a population of hippocampal cells whose high degree of anatomical and functional divergence make them suitable candidates for controlling the activity of large populations of principal neurons. GABAergic inhibitory interneurons play a major role in the synchronization of neuronal activity and are involved in the generation of large-scale network oscillations. Thus interneurons function as a clock; that dictates when principal cells fire during suprathreshold excitatory drive. Interneurons receive strong excitatory glutamatergic innervation via numerous anatomically distinct afferent projections and recent evidence has demonstrated that the molecular composition of both the AMPA-preferring class of glutamate receptors expressed at interneuron synapses are often distinct from those found at principal cell synapses. Furthermore, single inhibitory interneurons can synthesize distinct AMPA receptors with defined subunit composition and target them to synaptic domains innervated by different afferent inputs. Over the last year Dr McBains lab has investigated differential mechanisms of synaptic transmission onto hippocampal inhibitory interneurons and the role of intrinsic voltage-gated potassium channels in regulating interneuron excitability using high-resolution whole-cell patch clamp recording techniques in brain slices and organotypic hippocampal cultures. Specifically, we have demonstrated differential mechanisms of short and long-term plasticity, frequency dependent transmission, regulation of transmission by presynaptic metabotropic glutamate receptors and an interaction between short and long term changes in transmission at mossy fiber-interneuron and -pyramidal cell targets. Differential mechanisms of synaptic transmission between connected pairs of pyramidal neurons of the auditory cortex was also studied. We have also identified a subpopulation of inhibitory interneuron within the hilar/CA3 hippocampal subfields that is a target for histaminergic (H2) receptor modulation via PKA-phosphorylation of intrinsic voltage-dependent potassium channels formed by Kv3.2 subunits. Kv3.2 subunits endow interneurons with a fast-spiking phenotype. When PKA phosphorylated currents through Kv3.2 containing channels are blocked and interneuron action potential generation is shifted to a low frequency firing mode, which impacts not only interneuron function but the generation of coherent oscillations within the hippocampal principal cell populations. Modulation of gamma-frequency oscillations by muscarinic receptor activation in both wildtype and selective muscarine receptor knockouts was also studied.